An adequate medical response to the threat of pandemic influenza includes surveillance and isolation, a sufficient supply of effective antiviral drugs, and rapid development of a protective vaccine. Under optimal circumstances, production of enough vaccine to protect the US population would take 6 months. A lag time of 6 months between identification of a pandemic strain and an adequate supply of vaccine could result in devastating morbidity, mortality, and economic loss. A dose-sparing adjuvant that enabled a limited supply of vaccine to protect more people would diminish this problem. We have identified a small lipophilic molecule that can penetrate the intact stratum corneum and activate the dendritic cells (DC) in normal mouse skin. It enables resident DC to process adjuvant-free antigens injected into the skin and causes the DC to mature and migrate to the draining lymph node where they activate naove T cells. The speed with which this topical adjuvant increases protective antibody responses, its low cost, and physical independence of the vaccine antigen, suggest that it might be an ideal adjuvant for enhancing the protection afforded by a limiting supply of influenza vaccine. The aims of this Phase II application are to: 1) define the mechanism of action of this adjuvant;2) determine the efficacy and optimize its use as a topical adjuvant for an influenza vaccine in miniature pigs as a model for human skin;3) employ assays of transdermal transport across human skin ex vivo to optimize the conditions for its use as a topical adjuvant;and 4) perform pilot pre-clinical toxicity assays on this adjuvant. If our efforts are successful, the product will be an inexpensive small molecule, applied to the skin over a vaccine injection site that will make vaccines more effective. PUBLIC HEALTH RELEVANCE: The best public health response to pandemic influenza is an effective vaccine, but with current vaccine manufacturing capabilities it could take years to produce enough vaccine to protect the US population. We need vaccine additives that can extend the effective dose of a vaccine to cover more people. That is the goal of the proposed research.